POS0980 WHICH ACR RESPONSE DEFINITION SHOULD BE USED FOR DISEASE ACTIVITY CLAIMS IN APPROVAL STUDIES OF RHEUMATOID ARTHRITIS? A SYSTEMATIC EVALUATION
Authors: V. Konzett, A. Kerschbaumer, J. S. Smolen, D. Aletaha
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> An accurate evaluation of efficacy is key in any trial of novel pharmaceutical compounds. For rheumatoid arthritis (RA), the American College of Rheumatology 20, 50 and 70 response criteria (ACR20/50/70) were reported in all major clinical trials since 1995. Although clinically irrelevant, the ACR20 response still remains the primary endpoint required by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). <h3>Objectives</h3> In this analysis we explored how the stringency of the ACR response definitions (20%, 50% or 70%) differs with respect to their observed frequency and timing to inform potential future trial designs and regulatory decisions on required claims during the drug approval process in RA. <h3>Methods</h3> We conducted a systematic literature search in EMBASE, Medline and the Cochrane Library for multi-national, multi-center, phase 3 randomized drug trials (RCTs) investigating biological and targeted synthetic disease modifying anti-rheumatic drugs (bDMARDs/tsDMARDs) in adult RA patients. We included full articles published in English and reporting ACR responses for ≥3 time points over a 24-week study period. Baseline characteristics as well as ACR responses were extracted. For direct comparison of the response dynamics over time, we visualized ACR response rates on scales normalized to their maximum numerical responses observed during the respective trial (for details see legend). Calculation of p-values per outcome and timepoint for each treatment arm against placebo (Fisher's Exact test; α=0.05) allowed us to compare the discriminative capacity of the ACR responses between active treatment and placebo across all timepoints. Statistical analyses were done using R (V4.2.1, 2022, Vienna, Austria). <h3>Results</h3> We screened 12.457 articles (AK and VK) and selected 313 articles for full-text reading; we included 44 articles in the final analysis, which allowed for comparison of 95 treatment arms against placebo, investigating 8 different modes of action in DMARD-naïve patients as well as csDMARD and bDMARD insufficient responders (IR). The discriminative capacity of the ACR20 was highest across all timepoints analyzed (week 1 to 24), on average reaching 70% of the maximum response rate in the trial as early as by week 2 ('normalized' ACR response, Figure 1, Panel A). In contrast, ACR50 and 70 responses reached rates comparable to the ACR20 close to or at week 24, thus exhibiting slower response dynamics (Figure 1, Panel B). This effect was seen across all treatment arms (N=95) and independent of the mode of action, but slower for trials including treatment-IR patients compared with those assessing DMARD-naïve patients (Figure 1, Panel A). <h3>Conclusion</h3> The ACR20 response definition continues to be the most powerful discriminator between active treatment and placebo at early timepoints during trials; however, the discriminative capacity of the ACR50 and 70 definitions increases over the course of time. Our findings therefore support the use of these clinically more relevant response definitions at later but not early timepoints. <h3>REFERENCES:</h3> NIL. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.